title: Novel role of AMP-activated protein kinase signaling in cigarette smoke induction of IL-8 in human lung epithelial cells and lung inflammation in mice.
abstract: Cigarette smoke (CS) increases chemokine production in lung epithelial cells (LECs), but the pathways involved are not completely understood. AMP-activated protein kinase (AMPK), a crucial regulator of energy homeostasis, may modulate inflammation. Here, we show that cigarette smoke extract sequentially activated NADPH oxidase; increased intracellular reactive oxygen species (ROS) level; activated AMPK, NF-κB, and STAT3; and induced interleukin 8 (IL-8) in human LECs. Inhibition of NADPH oxidase activation by apocynin or siRNA targeting p47(phox) (a subunit of NADPH oxidase) attenuated the increased intracellular ROS level, AMPK activation, and IL-8 induction. Removal of intracellular ROS by N-acetylcysteine reduced the AMPK activation and IL-8 induction. Prevention of AMPK activation by Compound C or AMPK siRNA lessened the activation of both NF-κB and STAT3 and the induction of IL-8. Abrogation of the activation of NF-κB and STAT3 by BAY11-7085 and AG490, respectively, attenuated the IL-8 induction. We additionally show that chronic CS exposure in mice promoted AMPK phosphorylation and expression of MIP-2α (an IL-8 homolog) in LECs and lungs, as well as lung inflammation, all of which were reduced by Compound C treatment. Thus, a novel NADPH oxidase-dependent, ROS-sensitive AMPK signaling is important for CS-induced IL-8 production in LECs and possibly lung inflammation.
authors.affiliation: National Yang-Ming University Hospital, I-Lan, Taiwan.
authors.forename: Gau-Jun
authors.initials: GJ
authors.lastname: Tang
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Wang
authors.forename: Jen-Ying
authors.initials: JY
authors.lastname: Wang
authors.forename: Chih-Chieh
authors.initials: CC
authors.lastname: Lee
authors.forename: Hsu-Wen
authors.initials: HW
authors.lastname: Tseng
authors.forename: Yuh-Lin
authors.initials: YL
authors.lastname: Wu
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.forename: Tzong-Shyuan
authors.initials: TS
authors.lastname: Lee
authors.forename: Yu Ru
authors.initials: YR
authors.lastname: Kou
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010936:Plant Extracts / Q000008:administration & dosage; D011014:Pneumonia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects*
chemical_list: D000098:Acetophenones; D016209:Interleukin-8; D010936:Plant Extracts; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; C516138:dorsomorphin; C056165:acetovanillone; D019255:NADPH Oxidases; D055372:AMP-Activated Protein Kinases